Risk of Severe Acute Respiratory Syndrome Coronavirus 2 Infection Following Prior Infection or Vaccination.

BACKGROUND: The extent to which infection versus vaccination has conferred similarly durable severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunity during the Omicron era remains unclear. METHODS: In a cohort of 4496 adults under continued serological surveillance throughout the first year of Omicron-predominant SARS-CoV-2 transmission, we examined incidence of new infection among individuals whose last known antigenic exposure was either recent (<90 days) or remote (≥90 days) infection or vaccination. RESULTS: We adjudicated 2053 new-onset infections occurring between 15 December 2021 through 22 December 2022. In multivariable-adjusted analyses, compared to individuals whose last known exposure was remote vaccination, those with recent vaccination (odds ratio [OR], 0.82 [95% confidence interval {CI}, .73-.93]; P = .002) or recent infection (OR, 0.14 [95% CI, .05-.45]; P = .001) had lower risk for new infection within the subsequent 90-day period. Given a significant age interaction (P = .004), we found that remote infection compared to remote vaccination was associated with significantly greater new infection risk in persons aged ≥60 years (OR, 1.88 [95% CI, 1.13-3.14]; P = .015) with no difference seen in those <60 years (1.03 [95% CI, .69-1.53]; P = .88). CONCLUSIONS: During the initial year of Omicron, prior infection and vaccination both offered protection against new infection. However, remote prior infection was less protective than remote vaccination for individuals aged ≥60 years. In older adults, immunity gained from vaccination appeared more durable than immunity gained from infection.

Targeting PELP1 oncogenic signaling in TNBC with the small molecule inhibitor SMIP34.

PURPOSE: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Oncogenic PELP1 is frequently overexpressed in TNBC, and it has been demonstrated that PELP1 signaling is essential for TNBC progression. The therapeutic utility of targeting PELP1 in TNBC, however, remains unknown. In this study, we investigated the effectiveness of SMIP34, a recently developed PELP1 inhibitor for the treatment of TNBC. METHODS: To ascertain the impact of SMIP34 treatment, we used seven different TNBC models for testing cell viability, colony formation, invasion, apoptosis, and cell cycle analysis. Western blotting and RT-qPCR were used to determine the mechanistic insights of SMIP34 action. Using xenograft and PDX tumors, the ability of SMIP34 in suppressing proliferation was examined both ex vivo and in vivo. RESULTS: TNBC cells' viability, colony formation, and invasiveness were all decreased by SMIP34 in in vitro cell-based assays, while apoptosis was increased. SMIP34 treatment promoted the degradation of PELP1 through the proteasome pathway. RT-qPCR analyses confirmed that SMIP34 treatment downregulated PELP1 target genes. Further, SMIP34 treatment substantially downregulated PELP1 mediated extranuclear signaling including ERK, mTOR, S6 and 4EBP1. Mechanistic studies confirmed downregulation of PELP1 mediated ribosomal biogenesis functions including downregulation of cMyc and Rix complex proteins LAS1L, TEX-10, and SENP3. The proliferation of TNBC tumor tissues was decreased in explant experiments by SMIP34. Additionally, SMIP34 treatment markedly decreased tumor progression in both TNBC xenograft and PDX models. CONCLUSIONS: Together, these findings from in vitro, ex vivo, and in vivo models show that SMIP34 may be a useful therapeutic agent for inhibiting PELP1 signaling in TNBC.

Tuning the Dimensionality of Excitons in Colloidal Quantum Dot Molecules.

Electrically coupled quantum dots (QDs) can support unique optoelectronic properties arising from the superposition of single-particle excited states. Experimental methods for integrating colloidal QDs within the same nano-object, however, have remained elusive to the rational design. Here, we demonstrate a chemical strategy that allows for the assembling of colloidal QDs into coupled composites, where proximal interactions give rise to unique optoelectronic behavior. The assembly method employing "adhesive" surfactants was used to fabricate both homogeneous (e.g., CdS-CdS, PbS-PbS, CdSe-CdSe) and heterogeneous (e.g., PbS-CdS, CdS-CdSe) nanoparticle assemblies, exhibiting quasi-one-dimensional exciton fine structure. In addition, tunable mixing of single-particle exciton states was achieved for dimer-like assemblies of CdSe/CdS core-shell nanocrystals. The nanoparticle assembly mechanism was explained within the viscoelastic interaction theory adapted for molten-surface colloids. We expect that the present work will provide the synthetic and theoretical foundation needed for building assemblies of many inorganic nanocrystals.

Molecular patterns from a human gut-derived Lactobacillus strain suppress pathogenic infiltration of leukocytes into the central nervous system.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease that affects 2.5 million people worldwide. Growing evidence suggests that perturbation of the gut microbiota, the dense collection of microorganisms that colonize the gastrointestinal tract, plays a functional role in MS. Indeed, specific gut-resident bacteria are altered in patients with MS compared to healthy individuals, and colonization of gnotobiotic mice with MS-associated microbiota exacerbates preclinical models of MS. However, defining the molecular mechanisms by which gut commensals can remotely affect the neuroinflammatory process remains a critical gap in the field. METHODS: We utilized monophasic experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice and relapse-remitting EAE in SJL/J mice to test the effects of the products from a human gut-derived commensal strain of Lactobacillus paracasei (Lb). RESULTS: We report that Lb can ameliorate preclinical murine models of MS with both prophylactic and therapeutic administrations. Lb ameliorates disease through a Toll-like receptor 2-dependent mechanism via its microbe-associated molecular patterns that can be detected in the systemic circulation, are sufficient to downregulate chemokine production, and can reduce immune cell infiltration into the central nervous system (CNS). In addition, alterations in the gut microbiota mediated by Lb-associated molecular patterns are sufficient to provide partial protection against neuroinflammatory diseases. CONCLUSIONS: Local Lb modulation of the gut microbiota and the shedding of Lb-associated molecular patterns into the circulation may be important physiological signals to prevent aberrant peripheral immune cell infiltration into the CNS and have relevance to the development of new therapeutic strategies for MS.

Differential transcriptional profiles identify microglial- and macrophage-specific gene markers expressed during virus-induced neuroinflammation.

BACKGROUND: In the healthy central nervous system (CNS), microglia are found in a homeostatic state and peripheral macrophages are absent from the brain. Microglia play key roles in maintaining CNS homeostasis and acting as first responders to infection and inflammation, and peripheral macrophages infiltrate the CNS during neuroinflammation. Due to their distinct origins and functions, discrimination between these cell populations is essential to the comprehension of neuroinflammatory disorders. Studies comparing the gene profiles of microglia and peripheral macrophages, or macrophages in vitro-derived from bone marrow, under non-infectious conditions of the CNS, have revealed valuable microglial-specific genes. However, studies comparing gene profiles between CNS-infiltrating macrophages and microglia, when both are isolated from the CNS during viral-induced neuroinflammation, are lacking. METHODS: We isolated, via flow cytometry, microglia and infiltrating macrophages from the brains of Theiler's murine encephalomyelitis virus-infected C57BL/6 J mice and used RNA-Seq, followed by validation with qPCR, to examine the differential transcriptional profiles of these cells. We utilized primary literature defining subcellular localization to determine whether or not particular proteins extracted from the transcriptional profiles were expressed at the cell surface. The surface expression and cellular specificity of triggering receptor expressed on myeloid cells 1 (TREM-1) protein were examined via flow cytometry. We also examined the immune response gene profile within the transcriptional profiles of these isolated microglia and infiltrating macrophages. RESULTS: We have identified and validated new microglial- and macrophage-specific genes, encoding cell surface proteins, expressed at the peak of neuroinflammation. TREM-1 protein was confirmed to be expressed by infiltrating macrophages, not microglia, at the peak of neuroinflammation. We also identified both unique and redundant immune functions, through examination of the immune response gene profiles, of microglia and infiltrating macrophages during neurotropic viral infection. CONCLUSIONS: The differential expression of cell surface-specific genes during neuroinflammation can potentially be used to discriminate between microglia and macrophages as well as provide a resource that can be further utilized to target and manipulate specific cell responses during neuroinflammation.

Microglial cell depletion is fatal with low level picornavirus infection of the central nervous system.

Microglia are the only resident myeloid cell in the central nervous system (CNS) parenchyma, but the role of microglia in the context of neurotropic viral infection is poorly understood. Using different amounts of Theiler's murine encephalomyelitis virus (TMEV) in a preclinical model of epilepsy and PLX5622, a colony stimulating factor-1 receptor inhibitor that selectively depletes microglia in the CNS, we report that microglia-depleted, TMEV-infected mice develop seizures, manifest paralysis, and uniformly succumb to fatal encephalitis regardless of viral amount. CNS demyelination correlates with viral amount; however, viral amount does not correlate with axon damage and TMEV antigen in the CNS.

Balancing Two Cultures: American Indian/Alaska Native Medical Students' Perceptions of Academic Medicine Careers.

American Indians and Alaska Natives (AI/AN) remain underrepresented in the academic medicine workforce and little is known about cultivating AI/AN medical students' interest in academic medicine careers. Five structured focus groups were conducted including 20 medical students and 18 physicians. The discussion guide explored factors influencing AI/AN trainees' academic medicine career interest and recommended approaches to increase their pursuit of academia. Consensual qualitative research was employed to analyze transcripts. Our research revealed six facilitating factors, nine dissuading factors, and five recommendations towards cultivating AI/AN pursuit of academia. Facilitators included the opportunity to teach, serving as a role model/mentor, enhancing the AI/AN medical education pipeline, opportunities to influence institution, collegiality, and financial stability. Dissuading factors included limited information on academic career paths, politics, lack of credit for teaching and community service, isolation, self-doubt, lower salary, lack of positions in rural areas, lack of focus on clinical care for AI/AN communities, and research obligations. Recommendations included heighten career awareness, recognize the challenges in balancing AI/AN and academic cultures, collaborate with IHS on faculty recruitment strategies, identify concordant role models/mentors, and identify loan forgiveness programs. Similar to other diverse medical students', raising awareness of academic career opportunities especially regarding teaching and community scholarship, access to concordant role models/mentors, and supportive institutional climates can also foster AI/AN medical students' pursuit of academia. Unique strategies for AI/AN trainees include learning how to balance AI/AN and academic cultures, collaborating with IHS on faculty recruitment strategies, and increasing faculty opportunities in rural areas.

Characterization of nitrazine yellow as a photoacoustically active pH reporter molecule.

Throughout the fields of biomedical imaging, materials analysis, and routine chemical analysis, it is desirable to have a toolkit of molecules that can allow noninvasive/remote chemical sensing with minimal sample preparation. Here, we describe the photophysical properties involved in photoacoustic (PA) measurements and present a detailed analysis of the requirements and complications involved in PA sensing. We report the use of nitrazine yellow (NY) as a well-behaved PA pH reporter molecule. Both the basic and acidic forms of NY are photoacoustically well-behaved and allow for rapid and noninvasive measurement of pH in either transparent or turbid media. We also find that the serum protein-bound form of NY is photoacoustically well-behaved and should permit applications in noninvasive 3D imaging (e.g., the lymphatic system).

Resonance properties of Ag-ZnO nanostructures at terahertz frequencies.

Nanoantennas have been fabricated by scaling down traditional antenna designs using nanolithographic techniques and testing them at different optical wavelengths, these particular nanoantennas have shown responses in a broad range of frequencies going from visible wavelengths to the range of the terahertz. Some self-assembled nanostructures exist that exhibit similar shapes and properties to those of traditional antenna structures. In this work the emission and absorption properties of self-assembled nanostructures made of zinc oxide nanorods on silver nanowires, which resemble traditional dipole antennas, were measured and simulated in order to test their antenna performance. These structures show resonant properties in the 10-120 THz range, with the main resonance at 60 THz. The radiation pattern of these nanostructures was also obtained by numerical simulations, and it is shown that it can be tailored to increase or decrease its directivity as a function of the location of the energy source of excitation. Experimental measurements were performed by Raman spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR) in order to show existing vibrational frequencies at the resonant frequencies of the nanostructures, measurements were made from ~9 to 103 THz and the results were in agreement with the simulations. These characteristics make these metal-semiconductor Ag/ZnO nanostructures useful as self-assembled nanoantennas in applications such as terahertz spectroscopy and sensing at terahertz frequencies.

Mentorship and pursuit of academic medicine careers: a mixed methods study of residents from diverse backgrounds.

BACKGROUND: Mentorship influences career planning, academic productivity, professional satisfaction, and most notably, the pursuit of academic medicine careers. Little is known about the role of mentoring in recruiting Black/African American and Hispanic/Latino residents into academia. The objective of this study was to assess the influence of mentoring on academic medicine career choice among a cohort of racially and ethnically diverse residents. METHODS: A strategic convenience sample of U.S. residents attending national professional conferences between March and July 2010; residents completed a quantitative survey and a subset participated in focus groups. RESULTS: Of the 250 residents, 183 (73%) completed surveys and 48 participated in focus groups. Thirty-eight percent of residents were white, 31% Black/African American, 17% Asian/other, and 14% Hispanic/Latino. Most respondents (93%) reported that mentorship was important for entering academia, and 70% reported having sufficient mentorship to pursue academic careers. Three themes about mentorship emerged from focus groups: (1) qualities of successful mentorship models; (2) perceived benefits of mentorship; and (3) the value of racial/ethnic and gender concordance. Residents preferred mentors they selected rather than ones assigned to them, and expressed concern about faculty using checklists. Black/African American, Hispanic/Latino, and female residents described actively seeking out mentors of the same race/ethnicity and gender, but expressed difficulty finding such mentors. Lack of racial/ethnic concordance was perceived as an obstacle for minority mentees, requiring explanation of the context and nuances of their perspectives and situations to non-minority mentors. CONCLUSIONS: The majority of residents in this study reported having access to mentors. However, data show that the lack of diverse faculty mentors may impede diverse residents' satisfaction and benefit from mentorship relationships compared to white residents. These findings are important for residency programs striving to enhance resident mentorship and for institutions working to diversify their faculty and staff to achieve institutional excellence.

Eliminating LGBTIQQ Health Disparities: The Associated Roles of Electronic Health Records and Institutional Culture.

For all humans, sexual orientation and gender identity are essential elements of identity, informing how we plan and live our lives. The historic invisibility of sexual minorities in medicine has meant that these important aspects of their identities as patients have been ignored, with the result that these patients have been denied respect, culturally competent services, and proper treatment. Likely due to historic rejection and mistreatment, there is evidence of reluctance on the part of LGBT patients to disclose their sexual orientation (SO) or gender identity (GI) to their health care providers. There is some perception of risk in sharing SO and GI for many patients who have had bad prior experiences. Despite these risks, we argue that we can improve the quality of care provided this population only by encouraging them to self-identify and then using that information to improve quality of care. One strategy both to prompt patient self-identification and to store and use SO and GI data to improve care centers on the use of electronic health records. However, gathering SO and GI data in the EHR requires a workforce that knows both how to obtain and how to use that information. To develop these competencies, educational programs for health professionals must prepare students and educators to elicit and to use sexual orientation and gender identity information to improve care while simultaneously ensuring the safety of patients, trainees, and staff and faculty members as SO and GI become openly discussed and integral parts of ongoing medical discussion and care. As determination of SO and GI demographics becomes more common in health research, we will more fully understand the health risks for all the LGBTIQQ populations.

Melanoma: Does It Present Differently in Darker Skin Tones?

Introduction: There are vast differences in clinical presentations of melanoma across skin tones. Individuals with darker skin tones tend to have a higher prevalence of advanced-stage melanoma, which correlates with increased mortality. We designed this interactive workshop to increase nursing and medical trainees' awareness of the epidemiology, prevention, and treatment of melanoma in individuals of darker skin tones. Methods: The Kern model was used in the design, implementation, and evaluation of the workshop. The 75-minute workshop consisted of a PowerPoint presentation, video-based reflection activities, and case studies. Evaluation consisted of pre- and postworkshop questionnaires. The workshop was implemented two times among 63 nursing students, 11 medical students/residents, and six medical faculty. Results: Seventy-one participants completed the pre- and postworkshop evaluations. A comparison of pre- and postworkshop responses utilizing the Wilcoxon matched-pair signed rank test showed a statistically significant increase in learners' confidence to address each learning objective. Discussion: Through this interactive educational presentation, medical and nursing trainees can gain heightened awareness of melanoma across various skin tones, especially unique presentations in darker skin tones.

Home accessibility, living circumstances, stage of activity limitation, and nursing home use.

OBJECTIVE: To explore the influence of physical home and social environments and disability patterns on nursing home (NH) use. DESIGN: Longitudinal cohort study. Self- or proxy-reported perception of home environmental barriers accessibility, 5 stages expressing the severity and pattern of activities of daily living (ADLs) limitations, and other characteristics at baseline were applied to predict NH use within 2 years or prior to death through logistic regression. SETTING: General community. PARTICIPANTS: Population-based, community-dwelling individuals (N=7836; ≥70y) from the Second Longitudinal Study of Aging interviewed in 1994 with 2-year follow-up that was prospectively collected. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: NH use within 2 years. RESULTS: Perceptions of home environmental barriers and living alone were both associated with approximately 40% increased odds of NH use after adjustment for other factors. Compared with those with no limitations at ADL stage 0, the odds of NH use peaked for those with severe limitations at ADL stage III (odds ratio [OR]=3.12; 95% confidence interval [CI], 2.20-4.41), then declined sharply for those with total limitations at ADL stage IV (OR=.96; 95% CI, .33-2.81). Sensitivity analyses for missing NH use showed similar results. CONCLUSIONS: Accessibility of home environment, living circumstance, and ADL stage represent potentially modifiable targets for rehabilitation interventions for decreasing NH use in the aging U.S. population.

Mistreatment in Residency: Intervening With the REWIND Communication Tool.

Introduction: There is a lack of curricula addressing the alarming rates of resident physician mistreatment. As the ACGME works to address diversity, equity, and inclusion in GME, there has been increasing attention paid to the issue of mistreatment. Previous studies have noted a high prevalence of mistreatment within GME. Despite this, there are few published interventions to address the mistreatment of residents. We developed a workshop for residents to provide an overview of mistreatment in residency and teach them REWIND (relax, express, why, inquire, negotiate, determine), a communication tool to address mistreatment directly. Methods: We designed a 60-minute workshop for residents with didactics on mistreatment in GME, followed by three case discussions. Four case scenarios were developed to represent different types of mistreatment and situations. We implemented the workshop twice and asked participants to self-rate proficiency around the workshop objectives with pre- and postsurveys. Results: A total of 11 GME learners completed both the pre- and postsurveys between the two workshop implementations. GME learners who responded demonstrated significantly higher self-rated proficiency on each objective postworkshop compared to preworkshop (p < .05). Free responses on the survey demonstrated that participants particularly enjoyed the case discussions and wanted more practice with REWIND. Discussion: Our workshop improved participant self-rated proficiency around the mistreatment of resident physicians. The workshop can be used in the future as part of a multifaceted institutional response to mistreatment.

Primary adrenal insufficiency masking as an adrenal B-cell lymphoma.

We report here a woman in her 70s presenting with adrenal insufficiency secondary to a primary adrenal lymphoma. The patient had a previous history of aphthous ulcers on dexamethasone and was referred to endocrinology with symptoms of fatigue and orthostasis. Subsequent Cosyntropin stimulation showed primary adrenal insufficiency and adrenal CT demonstrated large infiltrative masses. Adrenal biopsy confirmed the diagnosis of primary adrenal lymphoma of the B-cell type. This case demonstrates the importance of including lymphoma in the differential diagnosis of adrenal insufficiency, particularly in the elderly population and in the setting of negative 21-hydroxlyase antibody results.

COVID-19 Education for Health Professionals Caring for Spanish-Speaking Patients.

Introduction: The COVID-19 pandemic has disproportionately affected Hispanics in the United States, who make up 18% of US inhabitants but 29% of COVID-19 cases as of June 2021. Recent studies have attributed higher COVID-19 infection, hospitalization, and death rates among Hispanics to social determinants of health. Given that the majority of US Hispanics are bilingual or Spanish-dominant, it is imperative for health care providers to be prepared to discuss COVID-19 prevention and treatment in Spanish. Methods: We developed an interactive workshop aimed at increasing health professionals' confidence in discussing COVID-19 prevention, risk factors, and treatments with Spanish-speaking patients. Learners were expected to have an intermediate level or higher proficiency in medical Spanish. The workshop consisted of a PowerPoint presentation and English/Spanish scripts to facilitate interactive learning. The workshop was evaluated using a postworkshop questionnaire to assess learners' perceived confidence in communicating with Spanish-speaking patients. Results: The workshop was implemented with 70 participants, who had diverse ethnoracial identities and professional roles, at five different medical schools. Fifty-three participants completed the postworkshop questionnaire. More than 50% reported near complete to complete confidence in meeting the three learning objectives. Discussion: With Hispanics being the largest non-White ethnoracial group in the US and being disproportionally affected by COVID-19, it is essential for health professionals to access training tools that allow them to practice medical Spanish. This module can uniquely aid in the preparation of health professionals caring for Spanish-speaking patients who present with COVID-19 symptoms.

Office of Diversity, Equity, and Inclusion: Engagement and Leadership Opportunities for Trainees.

Introduction: To achieve a healthier future for all, improving diversity through efforts such as diversifying faculty and leadership in academic medicine is imperative. Therefore, medical trainees (medical students, residents, fellows) from groups underrepresented in medicine (UiM) are encouraged to pursue academic careers and have opportunities to gain faculty leadership skills during their training. Trainees also need exposure to the leadership positions within various offices of an academic institution such as the Office of Diversity, Equity, and Inclusion (DEI). The goal of this module is to expose UiM trainees to the Office of DEI and leadership competencies that can be obtained via service and leadership opportunities with it. Methods: The Kern model was used in the development, implementation, and evaluation of this 75-minute workshop. The workshop consisted of a PowerPoint presentation, reflection exercises, and case discussion to raise trainees' awareness of the Office of DEI and opportunities to become engaged with and develop faculty leadership competencies through the office. Results: Sixty-six diverse learners across three sites completed pre- and postworkshop surveys. Ninety-five percent of participants agreed or strongly agreed that the learning objectives of the workshop had been met. Discussion: Overall, this interactive workshop facilitated learners' awareness of the responsibilities of the Office of DEI and opportunities for learners to develop faculty leadership competencies through engagement. Although primarily evaluated among medical students, the module can be of use to learners and faculty of other health professions programs with an Office of DEI.

LGBTQ+ Worker Protections: Implications for Academic Medicine Today and in the Future.

The Supreme Court's 2020 ruling prohibiting workplace discrimination based on sexual orientation or gender identity ( Bostock v Clayton County ) offers new legal protections for LGBTQ+ employees and allies and new opportunities for academic medicine to advance LGBTQ+ inclusion at their institutions. In this perspective piece, the authors examine the history of LGBTQ+ community recognition, tolerance, protections, and ongoing inclusion and the advocacy efforts led by LGBTQ+ patients, community activists, and medical colleagues. They also examine the current limitations of the court's ruling and recommend future actions to advance workplace and health equity. While recent advancements in equality have not erased chronic barriers to inclusion and advancement, they can pave the way for leaders in research, education, and clinical care to shape national health guidelines and policies that impact the health of all Americans.

A First-in-Class Inhibitor of ER Coregulator PELP1 Targets ER+ Breast Cancer.

Most patients with estrogen receptor alpha-positive (ER+) breast cancers initially respond to treatment but eventually develop therapy resistance with disease progression. Overexpression of oncogenic ER coregulators, including proline, glutamic acid, and leucine-rich protein 1 (PELP1), are implicated in breast cancer progression. The lack of small molecules that inhibits PELP1 represents a major knowledge gap. Here, using a yeast-two-hybrid screen, we identified novel peptide inhibitors of PELP1 (PIP). Biochemical assays demonstrated that one of these peptides, PIP1, directly interacted with PELP1 to block PELP1 oncogenic functions. Computational modeling of PIP1 revealed key residues contributing to its activity and facilitated the development of a small-molecule inhibitor of PELP1, SMIP34, and further analyses confirmed that SMIP34 directly bound to PELP1. In breast cancer cells, SMIP34 reduced cell growth in a dose-dependent manner. SMIP34 inhibited proliferation of not only wild-type (WT) but also mutant (MT) ER+ and therapy-resistant breast cancer cells, in part by inducing PELP1 degradation via the proteasome pathway. RNA sequencing analyses showed that SMIP34 treatment altered the expression of genes associated with estrogen response, cell cycle, and apoptosis pathways. In cell line-derived and patient-derived xenografts of both WT and MT ER+ breast cancer models, SMIP34 reduced proliferation and significantly suppressed tumor progression. Collectively, these results demonstrate SMIP34 as a first-in-class inhibitor of oncogenic PELP1 signaling in advanced breast cancer. SIGNIFICANCE: Development of a novel inhibitor of oncogenic PELP1 provides potential therapeutic avenues for treating therapy-resistant, advanced ER+ breast cancer.